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Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation
Daniel O. Kechele, … , P. Kay Lund, Kathleen M. Caron
Daniel O. Kechele, … , P. Kay Lund, Kathleen M. Caron
Published January 17, 2017
Citation Information: J Clin Invest. 2017;127(2):593-607. https://doi.org/10.1172/JCI87588.
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Research Article Gastroenterology

Orphan Gpr182 suppresses ERK-mediated intestinal proliferation during regeneration and adenoma formation

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Abstract

Orphan GPCRs provide an opportunity to identify potential pharmacological targets, yet their expression patterns and physiological functions remain challenging to elucidate. Here, we have used a genetically engineered knockin reporter mouse to map the expression pattern of the Gpr182 during development and adulthood. We observed that Gpr182 is expressed at the crypt base throughout the small intestine, where it is enriched in crypt base columnar stem cells, one of the most active stem cell populations in the body. Gpr182 knockdown had no effect on homeostatic intestinal proliferation in vivo, but led to marked increases in proliferation during intestinal regeneration following irradiation-induced injury. In the ApcMin mouse model, which forms spontaneous intestinal adenomas, reductions in Gpr182 led to more adenomas and decreased survival. Loss of Gpr182 enhanced organoid growth efficiency ex vivo in an EGF-dependent manner. Gpr182 reduction led to increased activation of ERK1/2 in basal and challenge models, demonstrating a potential role for this orphan GPCR in regulating the proliferative capacity of the intestine. Importantly, GPR182 expression was profoundly reduced in numerous human carcinomas, including colon adenocarcinoma. Together, these results implicate Gpr182 as a negative regulator of intestinal MAPK signaling–induced proliferation, particularly during regeneration and adenoma formation.

Authors

Daniel O. Kechele, R. Eric Blue, Bailey Zwarycz, Scott T. Espenschied, Amanda T. Mah, Marni B. Siegel, Charles M. Perou, Shengli Ding, Scott T. Magness, P. Kay Lund, Kathleen M. Caron

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Figure 1

Murine Gpr182 expression profile during development and adulthood.

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Murine Gpr182 expression profile during development and adulthood.
(A) T...
(A) Targeting vector of the Gpr182tm2a(KOMP)Wtsi/+ lacZ reporter mouse model (29, 62, 63). The GPR182 protein–coding region is shaded in pink. mGPR182, murine GPR182. (B) Whole-mount X-gal staining of E8 Gpr182lacZ/lacZ embryo. DA, dorsal aorta; VV, vitelline vein. (C) Optical projection tomography of whole-mount X-gal–stained WT and Gpr182lacZ/lacZ E13.5 embryos. X-Gal staining in Gpr182lacZ/lacZ E13.5 heart (D) and E17.5 lung, kidney, liver, yolk sac, and stomach, pancreas, and duodenum (E). Representative Gpr182 lacZ expression in adult heart (F), lung (G), kidney (H), liver (I), glandular stomach (J), and colon (K) stained with X-gal and/or β-gal (green). Sections were costained with DAPI (purple) and either the endothelial marker CD31 (F) or the podocyte marker podoplanin (PDPN) (H). X-Gal–stained sections were counterstained with eosin (F–H) or Neutral Red (D and I–K). Scale bars: 200 μm (B and D), 1 mm (C, E, and K), and 100 μm (F–J).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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